Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN([CH:5]([SH:7])C)C.C(=O)([O-])[O-].[K+].[K+].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[CH3:24][N:25]([CH3:28])[CH:26]=O>O>[CH3:24][N:25]([CH3:28])[CH2:26][CH2:5][S:7][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN(C)C=O
Reactant: CC(S)N(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN(C)CCSc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of N,N-dimethylaminoethanethiol hydrochloride (2.9 g, 14 mmol) in N,N-dimethylformamide (DMF) (70 mL) is added potassium carbonate (19 g, 140 mmol), followed by 4-fluoronitrobenzene (1.5 mL, 14 mmol). After stirring overnight at room temperature, the reaction mixture is diluted with water and extracted 3× with ethyl acetate. The combined extracts were washed five times with water and with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude oil is purified by flash chromatography (Isco 40 g Redi-Sep column, MeOH/CHCl3) to give N,N-dimethyl-N-{2-[(4-nitrophenyl)thio]ethyl}amine (2.3 g, 72%) as a golden oil.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:24])[N:15]([CH3:23])[CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH:8]=2)=[C:4]([F:27])[CH:3]=1.[C:28]1([CH2:34][C:35]([N:37]=[C:38]=[O:39])=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OCC)C.CCCCCC>O1CCCC1.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1N=CN=C(NC(N2CCCC2)=O)C=1>[F:27][C:4]1[CH:3]=[C:2]([NH:1][C:38]([NH:37][C:35](=[O:36])[CH2:34][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:39])[CH:26]=[CH:25][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:24])[N:15]([CH3:23])[CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[CH:8]=1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCCC3)ncn2)c(F)c1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1
Reaction time: 1 h
Yield: 88.1 %

Procedure:
3-[4-(4-Amino-2-fluorophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (50.0 mg) was dissolved in tetrahydrofuran (2 ml) under a nitrogen atmosphere, and then a solution of phenylacetyl isocyanate in toluene (0.80 ml, 0.5 M solution in toluene, Production Example 1) was added thereto, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:ethanol=9:1) Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (1 ml)-hexane (0,5 ml) was added to suspend. The solid was filtered off and dried under aeration to provide the titled compound (63.1 mg, 88.1%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:21][N:22]1[CH:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[N:23]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:27]([C:24]3[CH:25]=[CH:26][N:22]([CH3:21])[N:23]=3)=[O:28])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: Cn1ccc(C(=O)Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccn(C)n2)CC1
Reaction time: 2 h

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with 1-methyl-1H-pyrazole-3-carbonyl chloride (0.022 g, 0.16 mmol) and triethylamine (0.058 mL, 0.41 mmol) in methylene chloride (1.0 mL) at room temperature and the resulting mixture was stirred for 2 hrs. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired porduct (32 mg, 78%). LCMS calculated for C20H21ClN5O2 (M+H)+: m/z=398.1; Found: 398.1.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH:16]=[CH:17][C@@H:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[OH:23]O>O>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][CH:13]5[C:14]([CH:16]=[CH:17][C@:18]2([OH:23])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15]
Reactant: OO
Reactant: COc1ccc2c3c1O[C@H]1C(=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@]314
Solvent: O
Product: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314

Procedure:
In the first method of this invention, codeinone is reacted with hydrogen peroxide in water in the presence of an acid at about 15° to about 70° C. for a period of time depending on the scale of the reaction to afford 14-hydroxycodeinone in good yield. 14-Hydroxycodeinone so produced is hydrogenated in the same reaction media with a catalyst to afford oxycodone in good yield. Preferably the temperature is between about 40° to about 50° C. and the acid is formic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[NH:5][CH:6]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[CH3:2].Cl.[C:27](OCC)(=O)[CH3:28].CCCCCC>CC(C)=O.O>[CH2:1]([O:3][C:4]([N:5]1[CH:28]=[CH:27][C:21]2[C:16](=[CH:17][C:18]([O:23][CH3:24])=[C:19]([OH:22])[CH:20]=2)[CH:6]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:25])[CH3:2]
Reactant: CCOC(=O)NC(Cc1cccc(OC)c1)c1ccc(O)c(OC)c1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCCCCC
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)N1C=Cc2cc(O)c(OC)cc2C1Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37 %

Procedure:
To a stirred solution of (2,2-dimethoxy-ethyl)-[1-(4-hydroxy-3-methoxy-phenyl)-2-(3-methoxy-phenyl)-ethyl-carbamic acid ethyl ester (3.7 g, 8.55 mmol) in acetone (150 mL) was added 6N hydrochloric acid (38 mL) at 0° C. The reaction mixture was stirred at room temperature for 15 hrs. The mixture was diluted with water. The solvent was evaporated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (80 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) afforded 6-hydroxy-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (1.17, 37% yield) as a colorless oil.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:3]=1
Reactant: CCOC(=O)CC(=O)c1cccnc1
Reactant: CCOC(=O)CCCCCN
Product: CCOC(=O)C=C(NCCCCCC(=O)OCC)c1cccnc1

Procedure:
A mixture of 196 mg of ethyl nicotinoylacetate and 192 mg of ethyl 6-aminocaproate is heated at 120°-130° under nitrogen for 18 hours. The product is purified by preparative TLC (silica gel; chloroform, ethyl acetate 9.1) to yield ethyl β-(3-pyridyl)-β-(5-ethoxycarbonylpentylamino)acrylate;Rf =0.3.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[N:3]=1.Cl.[NH2:29][C:30]1[C:35]([C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])=[CH:34][CH:33]=[C:32]([NH:42][CH:43]2[CH2:48][CH2:47][CH2:46][NH:45][CH2:44]2)[N:31]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:29][C:30]1[C:35]([C:36](=[O:41])[C:37]([F:39])([F:40])[F:38])=[CH:34][CH:33]=[C:32]([NH:42][CH:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:2]3[N:7]4[N:8]=[C:9]([CH:11]5[CH2:16][CH2:15][N:14]([CH:17]([CH3:18])[CH3:19])[CH2:13][CH2:12]5)[N:10]=[C:6]4[CH:5]=[C:4]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[F:27])[N:3]=3)[CH2:44]2)[N:31]=1
Reactant: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(N4CCCC(Nc5ccc(C(=O)C(F)(F)F)c(N)n5)C4)n3n2)CC1
Temperature: 130 °C

Procedure:
80 mg (0.2 mmol) of 5-chloro-7-(2,4-difluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine, 81.2 mg (0.24 mmol) of 1-[2-amino-6-(piperidin-3-ylamino)pyridin-3-yl]-2,2,2-trifluoroethanone hydrochloride (Example 22A) and 0.213 ml (1.23 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 56 mg (42% of theory) of the product as a solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[N:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[C:49]=[O:50]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:51]([NH:48][C:49]([N:43]1[CH2:44][CH2:45][CH:40]([CH2:39][C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:46])[CH2:41][CH2:42]1)=[O:50])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(C)N=C=O
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 48 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 2-isocyanato-2-methyl-propane as starting materials in 48% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.32 (m, 2H), 8.13 (s, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.22 (d, 1H), 7.09 (m, 1H), 7.01 (d, 1H), 6.89 (d, 1H), 6.75 (d, 1H), 5.71 (s, 1H), 3.91 (d, 2H), 2.90 (m, 2H), 2.82 (m, 2H), 2.61 (m, 2H), 2.25 (d, 2H), 1.90 (m, 1H), 1.62 (m, 2H), 1.23 (s, 9H), 1.10 (m, 2H). LCMS for C30H37ClN7O2 (M+H)+: m/z=562.3.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][N:10]2[C:14]([CH3:15])=[CH:13][C:12]([C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]2[CH3:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[C:1]1([S:7]([CH2:8][CH2:9][N:10]2[C:14]([CH3:15])=[CH:13][C:12]([C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]2[CH3:24])=[O:33])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(C(=O)c2ccccc2)c(C)n1CCSc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(C(=O)c2ccccc2)c(C)n1CCS(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
In 15 ml of methylene chloride was dissolved 589 mg (1.76 mmoles) of 2-(3-benzoyl-2,5-dimethylpyrrol-1-yl)ethyl phenyl sulfide, and 350 mg (1.72 mmoles) of m-chloroperbenzoic acid (85% purity) was added. The mixture was stirred at room temperature for 16 hours. The organic layer was washed with a 1.0 N aqueous solution of sodium hydroxide, and then water, dried, and concentrated, and chromatographed on a column of silic gel using benzene/ethyl acetate as an eluent to afford compound (410)(562 mg, 1.60 mmoles, 91%).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[NH:5][C:4](=[O:10])[CH:3]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15].Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:5]2[C:4](=[O:10])[CH:3]=[C:2](/[N:1]=[CH:16]/[N:14]([CH3:13])[CH3:15])[N:7]([CH3:8])[C:6]2=[O:9])=[CH:22][CH:23]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(OC)N(C)C
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)cc(/N=C/N(C)C)n(C)c2=O)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 26.5 %

Procedure:
To a solution of 6-amino-1-methylpyrimidine-2,4(1H,3H)-dione (13.1 g, 92.9 mmol) in DMF (200 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (13 mL, 97.9 mmol) and the mixture was stirred at 40° C. for 3 h. Then 1-(chloromethyl)-4-methoxybenzene (15.05 mL, 111.5 mmol) was added followed by potassium carbonate (25.64 g, 0.186 mmol) and DMF (100 mL), the resulting mixture was stirred at 80° C. for 48 h. The reaction was cooled and diluted with ethyl acetate. The organic phase was washed with brine, dried and concentrated to give a crude product which was purified by silica gel chromatography eluting with methanol/DCM (1:80 to 1:20) to give (E)-N′-(1-(4-methoxybenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide (7.8 g, 26.5% yield) as yellow solid. LCMS retention time 1.023 min; LCMS MH+ 317.
Reaction SMILES: [K+].[Br-].Br[C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([O:19][C:20](C)(C)[CH3:21])=[O:18])=[C:12]3[CH2:11][N:10]=[C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:8]=2[CH:30]=1.N1C2C=CC=CC=2C=[CH:34][CH:33]=N1.[CH3:42]COC(C)=O>>[CH2:20]([O:19][C:17]([C:16]1[N:15]=[CH:14][N:13]2[C:12]=1[CH:11]([CH3:42])[N:10]=[C:9]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:8]1[CH:30]=[C:4]([C:33]#[CH:34])[CH:5]=[CH:6][C:7]2=1)=[O:18])[CH3:21]
Reactant: CCOC(C)=O
Reactant: C1=Cc2ccccc2NN=C1
Reactant: CC(C)(C)OC(=O)c1ncn2c1CN=C(c1ccccc1)c1cc(Br)ccc1-2
Agent: [Br-]
Agent: [K+]
Product: C#Cc1ccc2c(c1)C(c1ccccc1)=NC(C)c1c(C(=O)OCC)ncn1-2

Procedure:
{1-[4-Bromo-2-(2-fluoro-benzoyl)-phenylcarbamoyl-ethyl}-carbamic acid tert-butyl ester 116. To a stirred solution of (2-amino-5-bromophenyl)-(2-fluoro-phenyl)-methanone (60 g, 204 mmol) 115 and the N-Boc-L-alanine 107 (38.59 g, 204 mmol) in CH2Cl2 (500 mL) was added dicyclohexylcarbodiimide (DCC) (42.09 g, 204 mmol) in CH2Cl2 (200 mL) dropwise, over a 30 min period at 0° C. The reaction mixture was allowed to stir an additional 8 h at rt. The dicyclohexyl urea which formed was filtered off and the filtrate concentrated under reduced pressure. The crude solid residue 116 was purified by recrystallization from hexane and EtOAc to afford 116 (74.9 g, 79%) mp 158-159° C.; IR (KBr, cm−1) 3332, 2931, 255, 1694, 1643, 1613, 1582, 1537, 1450; 1H NMR (CDCl3) δ 11.68 (s, 1 H), 8.71 (d, J=9.0 Hz, 1 H), 7.69 (dd, J=9.0, 2.3 Hz, 1 H), 7.55-7.62 (m, 2 H), 7.46 (td, J=7.6, 1.4 Hz, 1 H), 7.30 (t, J=7.5 Hz, 1 H), 7.21 (t, J=9.1 Hz, 1 H), 5.13 (b, 1 H), 4.37 (b, 1 H), 1.51 (d, J=7.2 Hz, 3 H), 1.45 (s, 9H). MS (EI) m/e (relative intensity) 467 (M++2, 14), 466 (M++1, 44), 465 (M+, 14), 464 (42), 329 (15), 321 (60), 295 (100), 224 (26); [α]26D=−59.1 (c 0.51, EtOAc).
Reaction SMILES: [O:1]=[C:2]([N:23]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7](=[O:21])[CH2:6][C:5]1=[O:22].Br[CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[N:37]=1>CN(C=O)C.C1(C)C=CC=CC=1>[O:22]=[C:5]1[N:4]([CH2:3][C:2](=[O:1])[N:23]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7](=[O:21])[CH:6]1[CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[N:37]=1
Reactant: O=C(CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)N1CCCCc2ccccc21
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1nc(CC2C(=O)N(CC(=O)N3CCCCc4ccccc43)c3ccccc3N(c3ccccc3)C2=O)c2ccccc21

Procedure:
To a stirring solution of 1-[2-oxo-2-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)ethyl]-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (1.0 g, 2.28 mM) in 15 mL DMF at 0° C. was added 1.1 equiv. of 0.5 M solution of KN(TMS)2 in toluene. The resulting solution was stirred 10–30 min, then a solution of tert-butyl 3-(bromomethyl)-1H-indazole-1-carboxylate (0.78 g, 2.5 mM) in 3 mL DMF was added. The resulting solution was stirred 2 h at RT and then quenched with 5 mL of H2O. The reaction mixture was then poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer was separated, dried (MgSO4), and the solvents removed in vacuo. The resultant material was purified by silica gel flash column chromatography using hexanes/EtOAc 1/1 providing 1.4 g of white solid.
Reaction SMILES: C(OC([N:8]1[CH:13]=[C:12](Br)[CH:11]=[CH:10][CH:9]1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=O)(C)(C)C.[N:21]1([C:27]2[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[C:36]([O-:39])([O-])=[O:37].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(#N)C>[C:15]([O:39][C:36]([N:18]1[CH2:17][CH2:16][CH:15]([C:9]2[CH:10]=[CH:11][C:12]([C:30]3[CH:31]=[CH:32][C:27]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:28][CH:29]=3)=[CH:13][N:8]=2)[CH2:20][CH2:19]1)=[O:37])([CH3:20])([CH3:16])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1C=C(Br)C=CC1C1CCNCC1
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Agent: Cl[Pd]Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3ccc(N4CCOCC4)cc3)cn2)CC1
Temperature: 85 °C

Procedure:
5-Bromo-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1-carboxylic acid tert-butyl ester (0.6 g, 1.8 mmol), 4-morpholinylphenylboronic acid (400 mg, 1.9 mmol), bis(triphenylphosphine)-palladium(II)chloride (0.06 g, 0.09 mmol), 1 M Na2CO3 (4 ml) and acetonitrile (4 ml) were mixed in a 5 mL microwave vial. The reaction mixture was heated 1500 sec at 85° C. The water layer was removed. The acetonitrile phase was filtered and evaporated. The remainder was purified on a silicagel column with heptane: EtOAc (1:1) as eluent. 730 mg (98%) was isolated as the free base.
Reaction SMILES: C([N:8]=[C:9]([NH:42]C(OC(C)(C)C)=O)[NH:10][C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([NH:24][C:25]([NH:34]C(OC(C)(C)C)=O)=[N:26]C(OC(C)(C)C)=O)=[CH:18][CH:19]=3)[CH2:14][C:13]=2[CH:12]=1)(OC(C)(C)C)=O.[ClH:50]>C(Cl)Cl.CCO>[ClH:50].[ClH:50].[NH:10]([C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([NH:24][C:25]([NH2:34])=[NH:26])=[CH:18][CH:19]=3)[CH2:14][C:13]=2[CH:12]=1)[C:9]([NH2:42])=[NH:8]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc2c(c1)Cc1cc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)ccc1-2
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: N=C(N)Nc1ccc2c(c1)Cc1cc(NC(=N)N)ccc1-2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The N′,N″-di-BOC-guanidine (4a) (0.25 g, 0.4 mmol) was dissolved in CH2Cl2 (10 mL), diluted with dry EtOH (15 mL) and the chilled solution was saturated with dry HCl. The reaction was then kept stirring at room temperature for 3 days (drying tube), when by the product started forming a precipitate over time. After evaporating the solvent to dryness, the residue was washed with ether multiple times and was dried under vacuum at 50-60° C. over night to give whitish yellow solid of the bis-guanidine dihydrochloride (0.13 g, quantitative), mp>340° C. 1H-NMR (DMSO-d6): δ 3.95 (s, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.45 (s, 2H), 7.58 (br s, 8H), 7.95 (d, J=8.4 Hz, 2H), 10.23 (br s, 2H). 13C-NMR (DMSO-d6): δ 156.1, 156.1, 144.5, 138.6, 133.8, 123.3, 121.4, 120.9, 36.8. MS (EI): m/z 277 (M++1) (14), 252 (100). Anal. Calcd. for C15H16N6.2HCl-0.25C2H5OH (364.76): C % 51.04, H % 5.39, N % 23.04, Cl % 19.44. Found: C % 50.74, H % 5.26, N % 22.99, Cl % 19.87.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17]1[N:21]=[C:20]([CH3:22])[O:19][N:18]=1)[CH:11]=[CH:10]2.C[O:24][B:25](OC)[O:26]C.Cl>O1CCCC1>[CH3:22][C:20]1[O:19][N:18]=[C:17]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([B:25]([OH:26])[OH:24])[CH:16]=[CH:15]3)[N:21]=1
Reactant: Cc1nc(-c2ccc3cc(Br)ccc3c2)no1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc3cc(B(O)O)ccc3c2)no1
Temperature: -78 °C

Procedure:
4.76 ml n-butyllithium solution (1.6 M in hexane) are added dropwise to 1.00 g 3-(6-bromo-naphthalen-2-yl)-5-methyl-[1,2,4]oxadiazole in 15 ml of tetrahydrofuran at −78° C. The reaction mixture is stirred for another hour at −78° C., then 1.94 ml trimethylborate are added dropwise. Then the reaction mixture is left to heat up to ambient temperature and stirred overnight at this temperature. Then 9 ml 1 N hydrochloric acid are added while cooling with an ice bath. After 10 minutes at ambient temperature the tetrahydrofuran is distilled off in vacuo using the rotary evaporator and the flask residue is extracted with ethyl acetate. The combined organic extracts are dried on magnesium sulphate and evaporated down. The crude product is stirred with diisopropylether, suction filtered and dried.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5]CC)[O:2][CH2:3][CH3:4].[CH3:11][O:12][CH:13](OC)[C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([O:23][CH3:24])[CH:15]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:11][O:12][CH:13]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([O:23][CH3:24])[CH:15]=1)[P:1]([O:2][CH2:3][CH3:4])(=[O:5])[O:8][CH2:9][CH3:10]
Reactant: COc1cc(C(OC)OC)cc([N+](=O)[O-])c1
Reactant: CCOP(OCC)OCC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOP(=O)(OCC)C(OC)c1cc(OC)cc([N+](=O)[O-])c1
Yield: 86.8 %

Procedure:
Triethyl phosphite (0.98 ml, 5.7 mmol) was added dropwise to a solution of dimethyl acetal 27 (1.08 g, 4.7 mmol), boron trifluoride etherate (1.2 ml, 9.8 mmol) and CH2Cl2 (10 ml) at 0° C. After warming the reaction to room temperature overnight, the solution was partitioned with 3N HCl and the aqueous layer was washed with CH2Cl2 twice. The organic layers were washed with dilute NaHCO3, dried over Na2SO4, decanted and evaporated. The crude residue was purified on a silica gel column, eluting with 0-80% EtOAc/hexanes, to give 1.36 g (86%) phosphonate 28 as a slightly yellow oil.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].Cl[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[N:14]=2)[N:9]=[CH:8][C:7]=1[C:17]#[N:18]>C1COCC1>[CH:1]([O:4][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[N:14]=2)[N:9]=[CH:8][C:7]=1[C:17]#[N:18])([CH3:3])[CH3:2]
Reactant: CC(C)O
Reactant: Cc1ccc2ncc(C#N)c(Cl)c2n1
Solvent: C1CCOC1
Product: Cc1ccc2ncc(C#N)c(OC(C)C)c2n1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a 50 mL flask placed with KH (30%, 685 mg, 6.0 mmol, pre-washed with nHex) was added a solution of anhydrous isopropanol (0.76 mL, 10.0 mmol) in anhydrous THF (5 mL) at room temperature under argon. The reaction mixture was cooled to −20° C. 4-chloro-6-methyl-[1,5]naphthyridine-3-carbonitrile (407.0 mg, 2.0 mmol) in THF (8 mL) was added dropwise and the reaction mixture was stirred at −20° C. to r.t for 30 min. The reaction mixture was quenched with sat.NH4Cl and extracted with AcOEt (100 mL×3). The combined organic layers was dried over Na2SO4 and concentrated to give the crude product which was purified by flash column (AcOEt/Hex=1/3˜3/2) to give 4-Isopropoxy-6-methyl-[1,5]naphthyridine-3-carbonitrile as white solid (240.0, 52.8%) which was used in the next step without further purification.